CN105372343A - Method for separating and measuring substances related to memantine hydrochloride intermediate through gas chromatography - Google Patents
Method for separating and measuring substances related to memantine hydrochloride intermediate through gas chromatography Download PDFInfo
- Publication number
- CN105372343A CN105372343A CN201510650689.7A CN201510650689A CN105372343A CN 105372343 A CN105372343 A CN 105372343A CN 201510650689 A CN201510650689 A CN 201510650689A CN 105372343 A CN105372343 A CN 105372343A
- Authority
- CN
- China
- Prior art keywords
- separating
- memantine
- related substance
- temperature
- chromatographic column
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Pending
Links
Classifications
-
- G—PHYSICS
- G01—MEASURING; TESTING
- G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
- G01N30/00—Investigating or analysing materials by separation into components using adsorption, absorption or similar phenomena or using ion-exchange, e.g. chromatography or field flow fractionation
- G01N30/02—Column chromatography
-
- G—PHYSICS
- G01—MEASURING; TESTING
- G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
- G01N30/00—Investigating or analysing materials by separation into components using adsorption, absorption or similar phenomena or using ion-exchange, e.g. chromatography or field flow fractionation
- G01N30/02—Column chromatography
- G01N2030/022—Column chromatography characterised by the kind of separation mechanism
- G01N2030/025—Gas chromatography
Landscapes
- Physics & Mathematics (AREA)
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Analytical Chemistry (AREA)
- Biochemistry (AREA)
- General Health & Medical Sciences (AREA)
- General Physics & Mathematics (AREA)
- Immunology (AREA)
- Pathology (AREA)
- Other Investigation Or Analysis Of Materials By Electrical Means (AREA)
Abstract
The invention belongs to the field of analytical chemistry and discloses a method for separating and measuring a memantine hydrochloride intermediate 1-Amino-3, 5-dimethyladamantane hydrochloride and substances related to the intermediate through the gas chromatography. According to the method, a nonpolar capillary chromatographic column of polysiloxane series and a hydrogen flame ionization detector are adopted, the content of the memantine hydrochloride intermediate and the content of the substances related to the memantine hydrochloride intermediate can be measured quantitatively, thereby the reactant purity in the memantine hydrochloride synthesis process can be effectively controlled, occurrence of side reactions and generation of impurities are reduced, and the product yield is raised. The method is great in specificity, high in accuracy and simple and convenient in operation.
Description
Technical field
The invention belongs to analytical chemistry field, be specifically related to the method for vapor-phase chromatography separation determination memantine intermediate and related substance thereof.
Background technology
Memantine is the noncompetitive glutamate receptor antagonists of a kind of voltage-dependent, moderate affinity, blocked glutamic acid concentration pathologic can raise the neure damage caused, be mainly used in middle severe Alzheimer Disease patient.Memantine chemistry 1-Amino-3,5-dimethyladamantanehydrochloride by name, molecular formula is C
12h
21nHCl.Memantine intermediated chemistry is called 1,3-Dimethyladamantane, and molecular formula is C
12h
20, structural formula is:
In the process of synthetic hydrochloric acid Memantine, need the purity controlling some important intermediate, with the generation of the generation and impurity that reduce subsidiary reaction, thus improve product yield and purity.For memantine intermediate 1-Amino-3,5-dimethyladamantanehydrochloride, need the related substance controlled to have 3, i.e. 1-Bromoaladamantane (related substance A), structural formula is:
1-Methyladamantane (related substance B), structural formula is:
1-Bromo-3-Methyladamantane (related substance C), structural formula is:
Impurity removal in memantine intermediate is incomplete, will affect pharmaceutical purity and quality.Therefore, realize separation determination memantine intermediate and related substance thereof, the purity of reactant in synthetic hydrochloric acid Memantine process can be ensured, reduce the generation of subsidiary reaction, improve product yield and purity, have important practical significance in the production and quality control thereof of memantine.
Summary of the invention
The object of the present invention is to provide a kind of analysis memantine intermediate 1-Amino-3, the purity of 5-dimethyladamantanehydrochloride and be separated the method for its related substance, thus realize the separated island form of memantine intermediate and its related substance, to ensure the purity of memantine intermediate, reduce the generation of subsidiary reaction, improve product yield.
A kind of method measuring memantine intermediate related substance of the present invention, is select suitable solvent by sample dissolution, adopts polysiloxane-based capillary chromatographic column;
Above-mentioned said solvent can be one or more in methyl alcohol, ethanol, normal hexane or methylene chloride.
Above-mentioned said chromatographic column is selected from the brands such as Agilent, OHIOVALLEY or SGE.
Above-mentioned said chromatographic column is nonpolar or the polysiloxane-based capillary chromatographic column of low pole.
Method of separating and assaying of the present invention, can realize in accordance with the following methods:
1) get memantine intermediate and related substance thereof appropriate, dissolved with solvent respectively, be mixed with the sample solution of the hydrochloric memantine intermediate of every 1mL and related substance 0.1 ~ 1.0mg thereof.
2) arranging injector temperature is 150 ~ 250 DEG C, flow rate of carrier gas is 1.0 ~ 3.0mL/min, programmed temperature method, heating schedule is initial temperature 120 DEG C, constant temperature 1 ~ 10min, with the heating rate to 200 DEG C of 5 ~ 10 DEG C per minute, constant temperature 6 ~ 20min, detector temperature is 220 ~ 320 DEG C, and split ratio is 1:1 ~ 50:1.
3) get 1) sample solution 1 ~ 5 μ L, inject gas chromatograph, completes the separation determination of memantine intermediate and related substance thereof.Wherein:
The model of gas chromatograph, has no special requirements, and the chromatograph that the present invention adopts is Agilent6890N gas chromatograph
Flame ionization ditector
Chromatographic column: DB-1 capillary chromatographic column (Agilent, 30m × 0.32mm, 5 μm);
Injector temperature: 200 DEG C;
Detector temperature: 250 DEG C;
Carrier gas (nitrogen) flow velocity: 2.4mL/min;
Split ratio: 5.0:1;
Sampling volume: 1 μ L
Column temperature rise program:
The present invention utilizes vapor-phase chromatography, adopt polysiloxane-based nonpolar capillary chromatographic column (30m × 0.32mm, 5 μm), can fast and effeciently separation determination memantine intermediate and related substance thereof, the invention solves the separation determination problem of memantine intermediate and related substance thereof, thus decrease the generation of synthetic hydrochloric acid Memantine subsidiary reaction and the yield of product, the results are shown in accompanying drawing 1 ~ 5.
Accompanying drawing explanation
The gas chromatogram of solvent (normal hexane) when Fig. 1 is embodiment 1;
Memantine intermediate and related substance gas chromatogram thereof when Fig. 2 is embodiment 1;
Memantine intermediate gas chromatogram when Fig. 3 is embodiment 1;
Memantine intermediate and related substance gas chromatogram thereof when Fig. 4 is embodiment 2;
Memantine intermediate and related substance gas chromatogram thereof when Fig. 5 is embodiment 3.
Embodiment:
Following examples are used for understanding the present invention further, but are not limited to the scope of this enforcement.Below by way of example forms, the assay of the memantine intermediate that the present invention relates to and related substance detection method thereof are described in further detail, but this should be interpreted as that the scope of the above-mentioned theme of the present invention is only limitted to following example, all technology realized based on foregoing of the present invention all belong to scope of the present invention.
Embodiment 1
Instrument and condition
Chromatograph: Agilent6890N gas chromatograph;
Detecting device: flame ionization ditector;
Chromatographic column: DB-1 capillary chromatographic column (Agilent, 30m × 0.32mm, 5 μm);
Injector temperature: 200 DEG C;
Detector temperature: 250 DEG C;
Carrier gas (nitrogen) flow velocity: 2.4mL/min;
Split ratio: 5.0:1;
Sampling volume: 1 μ L
Column temperature rise program:
Experimental procedure
Get memantine intermediate and related substance thereof appropriate, with n-hexane dissolution, be mixed with the solution of the hydrochloric memantine intermediate of every 1mL and each 1.0mg of related substance thereof.Get above-mentioned memantine intermediate and related substance solution thereof appropriate, be mixed with system suitability solution; Separately get normal hexane as blank solution.Analyze by above-mentioned chromatographic condition, record chromatogram.The results are shown in accompanying drawing 1 ~ 3, Fig. 1 is blank solution chromatogram; In Fig. 2, the chromatographic peak of retention time 11.889min is memantine intermediate, and all the other chromatographic peaks are the related substance of memantine.In Fig. 3, the chromatographic peak of retention time 11.886min is memantine intermediate.Fig. 1 ~ Fig. 3 shows: method of the present invention, effectively can be separated with its related substance by memantine intermediate, and can accurately quantitatively detect, to calculate the purity of memantine intermediate.
Embodiment 2
Instrument and condition
Chromatograph: Agilent6890N gas chromatograph;
Detecting device: flame ionization ditector;
Chromatographic column: DB-1 capillary chromatographic column (Agilent, 30m × 0.32mm, 5 μm);
Injector temperature: 205 DEG C;
Detector temperature: 250 DEG C;
Carrier gas (nitrogen) flow velocity: 2.4mL/min;
Split ratio: 5.0:1;
Sampling volume: 1 μ L
Column temperature rise program:
Experimental procedure
Get memantine intermediate and related substance thereof appropriate, with n-hexane dissolution, be mixed with the solution of the hydrochloric memantine intermediate of every 1mL and each 1.0mg of related substance thereof.Get above-mentioned memantine intermediate and related substance solution thereof appropriate, be mixed with system suitability solution; Separately get normal hexane as blank solution.By above-mentioned memantine intermediate and related substance mixed solution, blank solution inject gas chromatograph respectively, analyze by above-mentioned chromatographic condition, record chromatogram.The chromatographic peak that the results are shown in retention time 11.887min in accompanying drawing 4, Fig. 4 is memantine intermediate, and all the other chromatographic peaks are the related substance of memantine.
Embodiment 3
Instrument and condition
Instrument and condition
Chromatograph: Agilent6890N gas chromatograph;
Detecting device: flame ionization ditector;
Chromatographic column: DB-1 capillary chromatographic column (Agilent, 30m × 0.32mm, 5 μm);
Injector temperature: 200 DEG C;
Detector temperature: 250 DEG C;
Carrier gas (nitrogen) flow velocity: 2.3mL/min;
Split ratio: 5.0:1;
Sampling volume: 1 μ L
Column temperature rise program:
Experimental procedure
Get memantine intermediate and related substance thereof appropriate, with n-hexane dissolution, be mixed with the solution of the hydrochloric memantine intermediate of every 1mL and each 1.0mg of related substance thereof.Get above-mentioned memantine intermediate and related substance solution thereof appropriate, be mixed with system suitability solution; Separately get normal hexane as blank solution.By above-mentioned memantine intermediate and related substance mixed solution, blank solution inject gas chromatograph respectively, analyze by above-mentioned chromatographic condition, record chromatogram.The chromatographic peak that the results are shown in retention time 12.093min in accompanying drawing 5, Fig. 5 is memantine intermediate, and all the other chromatographic peaks are the related substance of memantine.
The following items of the present invention to described memantine intermediate and Related substance method thereof is verified:
System suitability is tested
Get memantine intermediate and related substance thereof appropriate, use n-hexane dissolution respectively, be mixed with the test liquid of hydrochloric memantine intermediate and related substance thereof.Gas chromatographic analysis is carried out, record chromatogram by the chromatographic condition of embodiment 1.As seen from Figure 2 this, between related substance and main peak, degree of separation meets the requirements with this understanding.
Sample introduction replica test
By memantine intermediate test liquid, by the chromatographic condition of embodiment 1, repeat sample introduction 6 times, the repeatability of investigation method.Can be added by result, the method sample introduction repeatability is good.
Stability of solution
Get the test liquid of memantine intermediate and related substance thereof, by the chromatographic condition of embodiment 1, respectively at sample introduction after 0,1,2,4,6 hour, stability of solution when investigating this product quantitative measurement, from result, this sample solution was stablized in 6 hours.
Durability
By fine setting injector temperature, flow rate of carrier gas and chromatographic column brand isochromatic spectrum condition, we have investigated the durability of method further.Found that, the method is to good tolerance under the condition such as chromatographic column, injector temperature change ± 5 DEG C, flow rate of carrier gas change ± 0.1mL/min of different brands.Under different brands chromatographic column, different injector temperature, flow rate of carrier gas condition, memantine intermediate and related substance retention time thereof without marked change, and all can reach effective separation.
Detectability
Get memantine intermediate and related substance thereof appropriate, accurately weighed, use n-hexane dissolution sample respectively, be mixed with the test liquid of response, then precision to measure test liquid appropriate, stepwise dilution, investigates by the chromatographic condition sample introduction of embodiment 1.Memantine intermediate detectability data are as shown in the table:
Claims (10)
1. vapor-phase chromatography is separated the method detecting memantine intermediate and related substance thereof, it is characterized in that: with suitable solvent by sample dissolution, adopt polysiloxane-based capillary chromatographic column, and flame ionization ditector detects.
2. method of separating and assaying according to claim 1, solvent can be one or more in methyl alcohol, ethanol, normal hexane or methylene chloride.
3. method of separating and assaying according to claim 1, chromatographic column is selected from the chromatographic column that brand is Agilent, OHIOVALLEY or SGE.
4. method of separating and assaying according to claim 1, chromatographic column is nonpolar or the polysiloxane-based capillary chromatographic column of low pole.
5. method of separating and assaying according to claim 1, is characterized in that, comprises following step:
1) get memantine intermediate and related substance thereof appropriate, dissolved with solvent respectively, be mixed with the sample solution of the hydrochloric memantine intermediate of every 1mL and related substance 0.1 ~ 1.0mg thereof.
6.2) arranging injector temperature is 150 ~ 250 DEG C, flow rate of carrier gas is 1.0 ~ 3.0mL/min, programmed temperature method, heating schedule is initial temperature 120 DEG C, constant temperature 1 ~ 10min, with the heating rate to 200 DEG C of 5 ~ 10 DEG C per minute, constant temperature 6 ~ 20min, detector temperature is 220 ~ 320 DEG C, and split ratio is 1:1 ~ 50:1.
7.3) get 1) sample solution 1 ~ 5 μ L, inject gas chromatograph, completes the separation determination of memantine intermediate and related substance thereof.
8. method for separating and analyzing according to claim 5, step 2) said carrier gas is nitrogen or helium.
9. method for separating and analyzing according to claim 5, step 2) said detector temperature preferably 250 DEG C.
10. method for separating and analyzing according to claim 5, step 2) said programmed temperature method, preferred following heating schedule:
。
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201510650689.7A CN105372343A (en) | 2015-10-09 | 2015-10-09 | Method for separating and measuring substances related to memantine hydrochloride intermediate through gas chromatography |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201510650689.7A CN105372343A (en) | 2015-10-09 | 2015-10-09 | Method for separating and measuring substances related to memantine hydrochloride intermediate through gas chromatography |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN105372343A true CN105372343A (en) | 2016-03-02 |
Family
ID=55374725
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201510650689.7A Pending CN105372343A (en) | 2015-10-09 | 2015-10-09 | Method for separating and measuring substances related to memantine hydrochloride intermediate through gas chromatography |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN105372343A (en) |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN108918722A (en) * | 2018-08-02 | 2018-11-30 | 中国医科大学附属第医院 | A method of nmda receptor antagonist JCC-02 blood concentration is detected based on HPLC-MS/MS technology |
| CN116046926A (en) * | 2022-12-07 | 2023-05-02 | 合肥久诺医药科技有限公司 | Detection method of 1-bromo-3, 5-dimethyl adamantane related substances |
Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102531919A (en) * | 2011-11-09 | 2012-07-04 | 广东肇庆星湖生物科技股份有限公司 | Preparation method of memantinehydrochloride |
| CN103483205A (en) * | 2013-10-12 | 2014-01-01 | 合肥久诺医药科技有限公司 | Preparation method of high-purity memantine hydrochloride |
| CN103524353A (en) * | 2013-10-12 | 2014-01-22 | 合肥久诺医药科技有限公司 | Preparation method for high-purity memantine hydrochloride |
-
2015
- 2015-10-09 CN CN201510650689.7A patent/CN105372343A/en active Pending
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102531919A (en) * | 2011-11-09 | 2012-07-04 | 广东肇庆星湖生物科技股份有限公司 | Preparation method of memantinehydrochloride |
| CN103483205A (en) * | 2013-10-12 | 2014-01-01 | 合肥久诺医药科技有限公司 | Preparation method of high-purity memantine hydrochloride |
| CN103524353A (en) * | 2013-10-12 | 2014-01-22 | 合肥久诺医药科技有限公司 | Preparation method for high-purity memantine hydrochloride |
Non-Patent Citations (1)
| Title |
|---|
| LITI GRICE，ET AL: "Diamondoid hydrocarbon ratios as indicators of biodegradation in Australian crude oils", 《ORGANIC GEOCHEMISTRY》 * |
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN108918722A (en) * | 2018-08-02 | 2018-11-30 | 中国医科大学附属第医院 | A method of nmda receptor antagonist JCC-02 blood concentration is detected based on HPLC-MS/MS technology |
| CN108918722B (en) * | 2018-08-02 | 2021-04-23 | 中国医科大学附属第一医院 | Method for detecting NMDA receptor antagonist JCC-02 blood concentration based on HPLC-MS/MS technology |
| CN116046926A (en) * | 2022-12-07 | 2023-05-02 | 合肥久诺医药科技有限公司 | Detection method of 1-bromo-3, 5-dimethyl adamantane related substances |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN104655751B (en) | A kind of detect the method for organic solvent residual in dapoxetine | |
| CN105372343A (en) | Method for separating and measuring substances related to memantine hydrochloride intermediate through gas chromatography | |
| CN112730641B (en) | Ion chromatography determination method of N-methylpiperazine | |
| CN106033079B (en) | Method for detecting related substance imidazole in starting material F of dabigatran etexilate mesylate | |
| CN105467028A (en) | A method of separating and measuring optical isomers of a lurasidone intermediate by gas chromatography | |
| CN113125574A (en) | Method for separating and measuring related substances of memantine starting material by gas chromatography | |
| CN114965749B (en) | Detection method of related substances in Shubian bulk drug | |
| CN103645259B (en) | Method for simultaneously determining 4-amino-2-(2,6-dioxo-3-piperidyl)isoindoline-1,3-dione and related substances thereof | |
| CN105911155B (en) | Method for separating and measuring related substances of lurasidone hydrochloride intermediate by gas chromatography | |
| CN113607831B (en) | Detection method of 4-Boc-aminopiperidine related substance | |
| CN111624276B (en) | Method for simultaneously detecting genotoxic impurities 5-isoquinoline methyl sulfonate and 5-isoquinoline ethyl sulfonate in fasudil hydrochloride | |
| CN105301160A (en) | Method for measuring chemical purity of clinofibrate midbody by adopting gas chromatography separation | |
| CN111505163B (en) | Method for detecting phenethyl methane sulfonate substances | |
| CN103149314A (en) | Method for identification and content determination of 1, 2-propanediol in isosorbide mononitrate injection | |
| CN105467027A (en) | A method of separating and measuring compounds related to a minodronic acid intermediate through gas chromatography | |
| CN108254461B (en) | Novel detection method for taurocholic acid content and related substances | |
| CN112710762A (en) | Method for measuring residual quantity of dimethyl sulfate | |
| CN110824038A (en) | Liquid chromatography analysis method of 2,3,4, 6-tetra-O-trimethylsilyl-D-gluconolactone | |
| CN113984927B (en) | Gas chromatographic analysis method for related substances of triethyl methane tricarboxylate | |
| CN105044263A (en) | Gas chromatography test method for 4-ethoxy-2, 3-difluorophenol | |
| CN104330505B (en) | The assay method of residual solvent in a kind of calf serum de-protein injection | |
| CN113433249B (en) | Method for detecting minocycline intermediate related substances by high performance liquid chromatography | |
| CN109030652A (en) | A kind of high-efficiency liquid chromatography method for detecting of hexichol base oxethyl phosphine | |
| CN111103374B (en) | Method for measuring content of 2, 6-tetramethylpiperidine oxide in cinacalcet hydrochloride | |
| CN112034058B (en) | Method for detecting isomer impurities in vincamine |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| C06 | Publication | ||
| PB01 | Publication | ||
| SE01 | Entry into force of request for substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| WD01 | Invention patent application deemed withdrawn after publication |
Application publication date: 20160302 |
|
| WD01 | Invention patent application deemed withdrawn after publication |